RESUMO
Phosphaturic mesenchymal tumor (PMT) is a rare paraneoplastic syndrome characterized by renal phosphate wasting, hypophosphatemia, and bone calcification disorders. Complete surgical resection of the tumor is believed to be the most effective treatment measure. However, the diagnosis of PMT is very difficult because of its insidious and small size, especially, when it appears in subcutaneous tissue with a chronic non-healing wound. We report a rare case of a 38-year-old man with a chronic non-healing wound on the left hallux for approximately eight months. Plain radiographic images and magnetic resonance imaging (MRI) revealed a cystic radiolucent shadow in the left distal phalanx. Bone scan observations also showed increased uptake in the same location. Histologically, this tumor was composed of numerous spindle cells with clusters of giant cells. The serum FGF23 level was significantly higher before surgery, with higher FGF23 levels closer to the tumor. Reverse transcription polymerase chain reaction and immunohistochemistry further confirmed the high expression of FGF23 in tumors. These data suggest that FGF23 may be a potential causative factor of PMT. The serum FGF23 levels might be useful for the diagnosis of PMT and localization of the tumor. The tumor was CD56- and D2 to 40-positive and CD31-negative. The non-healing wound caused by PMT might be attributed to the invasive growth of the tumor, destruction of intercellular junctions, and decrease in the number of endothelial cells.
Assuntos
Hallux , Mesenquimoma , Neoplasias de Tecido Conjuntivo , Neoplasias de Tecidos Moles , Masculino , Humanos , Adulto , Neoplasias de Tecido Conjuntivo/diagnóstico , Neoplasias de Tecido Conjuntivo/metabolismo , Neoplasias de Tecido Conjuntivo/patologia , Hallux/patologia , Células Endoteliais , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/cirurgia , Mesenquimoma/diagnóstico , Mesenquimoma/metabolismo , Mesenquimoma/patologiaRESUMO
We summarize herein the literature data about molecular targeted therapies in sarcomas and conjunctive tissue intermediate malignancies. For each clinical setting, the level of evidence, the mechanism of action and the target are described. The two major axes include (i) identification of subgroups of tumors with druggable alteration irrespective of the histological diagnosis (e.g. NTRK), and (ii) druggable target of pathway related to the physiopathology of the tumor: denosumab and bone giant cell tumor, imatinib and soft tissue giant cell tumor, mTOR inhibitor and PECOMA.
Assuntos
Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular/métodos , Neoplasias de Tecido Conjuntivo/tratamento farmacológico , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Humanos , Mesilato de Imatinib , Neoplasias de Tecido Conjuntivo/metabolismo , Neoplasias de Tecido Conjuntivo/patologia , Sarcoma/metabolismo , Sarcoma/patologia , Neoplasias de Tecidos Moles/metabolismo , Neoplasias de Tecidos Moles/patologiaRESUMO
Extracellular matrix (ECM) plays a central and dynamic role in the creation of tumor microenvironment. Herein we discuss the emerging biophysical and biochemical aspects of ECM buildup and proteolysis in cancer niche formation. Dysregulated ECM remodeling by cancer cells facilitate irreversible proteolysis and crosslinking, which in turn influence cell signaling, micro environmental cues, angiogenesis and tissue biomechanics. Further, we introduce the emerging roles of cancer microbiome in aberrant tumor ECM remodeling and membrane bound nano-sized vesicles called exosomes in creation of distant pre-metastatic niches. A detailed molecular and biophysical understanding of the ECM morphologies and its components such as key enzymes, structural and signaling molecules are critical in identifying the next generation of therapeutic and diagnostic targets in cancer.
Assuntos
Matriz Extracelular/metabolismo , Neoplasias/metabolismo , Microambiente Tumoral , Animais , Progressão da Doença , Suscetibilidade a Doenças , Humanos , Microbiota , Neoplasias/etiologia , Neoplasias/patologia , Neoplasias/terapia , Neoplasias de Tecido Conjuntivo/etiologia , Neoplasias de Tecido Conjuntivo/metabolismo , Neoplasias de Tecido Conjuntivo/patologia , Neoplasias de Tecido Conjuntivo/terapia , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Proteólise , Transdução de SinaisRESUMO
The tumor microenvironment (TME) is a complex meshwork of extracellular matrix (ECM) macromolecules filled with a collection of cells including cancer-associated fibroblasts (CAFs), blood vessel associated smooth muscle cells, pericytes, endothelial cells, mesenchymal stem cells and a variety of immune cells. In tumors the homeostasis governing ECM synthesis and turnover is disturbed resulting in abnormal blood vessel formation and excessive fibrillar collagen accumulations of varying stiffness and organization. The disturbed ECM homeostasis opens up for new types of paracrine, cell-cell and cell-ECM interactions with large consequences for tumor growth, angiogenesis, metastasis, immune suppression and resistance to treatments. As a main producer of ECM and paracrine signals the CAF is a central cell type in these events. Whereas the paracrine signaling has been extensively studied in the context of tumor-stroma interactions, the nature of the numerous integrin-mediated cell-ECM interactions occurring in the TME remains understudied. In this review we will discuss and dissect the role of known and potential CAF interactions in the TME, during both tumorigenesis and chemoresistance-induced events, with a special focus on the "interaction landscape" in desmoplastic breast, lung and pancreatic cancers. As an example of the multifaceted mode of action of the stromal collagen receptor integrin α11ß1, we will summarize our current understanding on the role of this CAF-expressed integrin in these three tumor types.
Assuntos
Fibroblastos Associados a Câncer/metabolismo , Transformação Celular Neoplásica/metabolismo , Integrinas/metabolismo , Neoplasias de Tecido Conjuntivo/etiologia , Neoplasias de Tecido Conjuntivo/metabolismo , Animais , Biomarcadores Tumorais , Fibroblastos Associados a Câncer/patologia , Transformação Celular Neoplásica/genética , Suscetibilidade a Doenças , Fibroblastos , Humanos , Neoplasias de Tecido Conjuntivo/patologia , Especificidade de Órgãos , Microambiente Tumoral/genéticaAssuntos
Imunoglobulina G/metabolismo , Linfonodos/diagnóstico por imagem , Neoplasias de Tecido Conjuntivo/diagnóstico por imagem , Neoplasias de Tecido Conjuntivo/metabolismo , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Diabetes Mellitus Tipo 2/metabolismo , Fluordesoxiglucose F18 , Humanos , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Osteomalacia , Síndromes Paraneoplásicas , Tomografia por Emissão de PósitronsRESUMO
BACKGROUND/AIM: The objective of the present study was to determine the clinicopathological factors and treatment outcomes of patients suffering from mesenteric or retroperitoneal extragastrointestinal stromal tumors (EGISTs). MATERIALS AND METHODS: A detailed search in PubMed, using the key words "extragastrointestinal stromal tumors" and "EGIST", found eight studies fulfilling the criteria of this study. RESULTS: Thirty-six patients with a mesenteric and 24 patients with a retroperitoneal EGIST were analyzed, with a follow-up period ranging from 2 to 192 months. Retroperitoneal tumors presented as larger tumors than mesenteric ones, with 95% and 93% immunohistochemical positivity for CD117 antigen, respectively. Surgical resection was performed in 91% of cases, with 57% of patients with mesenteric and 70% of patients with retroperitoneal EGISTs being alive at the last follow-up. CONCLUSION: EGISTs most commonly are of considerable size and usually with a high mitotic count, rendering them high-risk tumors. Tumor necrosis, nuclear atypia, tumor histology, and mutations in the tyrosine kinase KIT or platelet-derived growth factor receptor A (PDGFRA) gene, seem to influence tumor behavior.
Assuntos
Mesentério/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias de Tecido Conjuntivo/patologia , Neoplasias Retroperitoneais/patologia , Células Estromais/patologia , Humanos , Imuno-Histoquímica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Neoplasias de Tecido Conjuntivo/genética , Neoplasias de Tecido Conjuntivo/metabolismo , Neoplasias de Tecido Conjuntivo/cirurgia , Neoplasias Retroperitoneais/genética , Neoplasias Retroperitoneais/metabolismo , Neoplasias Retroperitoneais/cirurgia , Fatores de Risco , Resultado do TratamentoRESUMO
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic condition in which phosphaturic mesenchymal tumors (PMTs) secrete high levels of fibroblast growth factor 23 (FGF23) into the circulation. This results in renal phosphate wasting, hypophosphatemia, muscle weakness, bone pain, and pathological fractures. Recent studies suggest that fibronectin-fibroblast growth factor receptor 1 (FN1-FGFR1) translocations may be a driver of tumorigenesis. We present a patient with TIO who also exhibited clinical findings suggestive of Cowden syndrome (CS), a rare autosomal dominant disorder characterized by numerous benign hamartomas, as well as an increased risk for multiple malignancies, such as thyroid cancer. While CS is a clinical diagnosis, most, but not all, harbor a mutation in the tumor suppressor gene PTEN. Genetic testing revealed a somatic FN1-FGFR1 translocation in the FGF23-producing tumor causing TIO; however, a germline PTEN mutation was not identified. To our knowledge, this is the first reported case of concurrent TIO and CS.
Assuntos
Síndrome do Hamartoma Múltiplo/complicações , Neoplasias de Tecido Conjuntivo/etiologia , Síndromes Paraneoplásicas/etiologia , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/biossíntese , Síndrome do Hamartoma Múltiplo/patologia , Síndrome do Hamartoma Múltiplo/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias de Tecido Conjuntivo/metabolismo , Osteomalacia , PTEN Fosfo-Hidrolase/genéticaRESUMO
Tumour-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare paraneoplastic disorder caused by tumours that secrete fibroblast growth factor 23 (FGF23). Owing to the role of FGF23 in renal phosphate handling and vitamin D synthesis, TIO is characterized by decreased renal tubular reabsorption of phosphate, by hypophosphataemia and by low levels of active vitamin D. Chronic hypophosphataemia ultimately results in osteomalacia (that is, inadequate bone mineralization). The diagnosis of TIO is usually suspected when serum phosphate levels are chronically low in the setting of bone pain, fragility fractures and muscle weakness. Locating the offending tumour can be very difficult, as the tumour is often very small and can be anywhere in the body. Surgical removal of the tumour is the only definitive treatment. When the tumour cannot be located or when complete resection is not possible, medical treatment with phosphate salts or active vitamin D is necessary. One of the most promising emerging treatments for unresectable tumours that cause TIO is the anti-FGF23 monoclonal antibody KRN23. The recent identification of a fusion of fibronectin and fibroblast growth factor receptor 1 (FGFR1) as a molecular driver in some tumours not only sheds light on the pathophysiology of TIO but also opens the door to a better understanding of the transcription, translocation, post-translational modification and secretion of FGF23, as well as suggesting approaches to targeted therapy. Further study will reveal if the FGFR1 pathway is also involved in tumours that do not harbour the translocation.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Hipofosfatemia/complicações , Neoplasias de Tecido Conjuntivo/diagnóstico , Osteomalacia/patologia , Fosfatos/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/genética , Fibronectinas/metabolismo , Fraturas Ósseas/diagnóstico , Fraturas Ósseas/etiologia , Humanos , Hipofosfatemia/sangue , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/diagnóstico , Debilidade Muscular/etiologia , Neoplasias de Tecido Conjuntivo/metabolismo , Neoplasias de Tecido Conjuntivo/fisiopatologia , Neoplasias de Tecido Conjuntivo/cirurgia , Osteomalacia/epidemiologia , Osteomalacia/metabolismo , Dor/diagnóstico , Dor/etiologia , Síndromes Paraneoplásicas/diagnóstico , Síndromes Paraneoplásicas/etiologia , Fosfatos/uso terapêutico , Processamento de Proteína Pós-Traducional/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Vitamina D/metabolismo , Vitamina D/uso terapêuticoRESUMO
The potential of peptide receptor radionuclide therapy (PRRT) is described in a case of recurrent inoperable phosphaturic mesenchymal tumor causing osteomalacia in the left basiocciput, for which the patient had undergone surgery twice previously. After one cycle of PRRT, there was good symptomatic improvement, with a modest reduction in uptake on both 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT suggesting a favorable response. Hence, treatment with a second cycle was considered. Being somatostatin receptor-avid, this rare group of tumors when inoperable or recurrent may potentially be targeted with PRRT. Well-tolerated and noninvasive, PRRT could evolve as a promising targeted treatment approach in this clinical setting. In summary, tumor-induced osteomalacia with 68Ga-DOTATATE-avid inoperable or recurrent tumor can be considered a potential clinical application for PRRT beyond neuroendocrine tumors.
Assuntos
Neoplasias de Tecido Conjuntivo/etiologia , Neoplasias de Tecido Conjuntivo/radioterapia , Octreotida/análogos & derivados , Compostos Organometálicos , Receptores de Somatostatina/metabolismo , Crânio , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias de Tecido Conjuntivo/diagnóstico por imagem , Neoplasias de Tecido Conjuntivo/metabolismo , Osteomalacia , Síndromes Paraneoplásicas , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , RecidivaRESUMO
Tumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic disorder and fibroblast growth factor 23 (FGF23) plays a key role in its pathogenesis. This study was conducted to describe a novel FGF23 detecting procedure and describe clinical features of the disease. Fourteen TIO cases were retrieved and FGF23 expression was measured by quantitative ELISA-like immunohistochemistry using formalin-fixed and paraffin-embedded tissues. As summarized from 14 TIO cases, clinical features of TIO were long-standing history of osteomalacia, hypophosphatemia, and urinary phosphate wasting. The associated tumors were mostly benign phosphaturic mesenchymal tumors mixed connective tissue variant (PMTMCT) which could be located anywhere on the body, and most of them could be localized by conventional examinations and octreotide scanning. By quantitative ELISA-like immunohistochemistry, all the 14 TIO cases had high FGF23 expression (median 0.69, 25%-75% interquartile 0.57-1.10, compared with 26 non-TIO tumors of median 0.07, 25%-75% interquartile 0.05-0.11, p < 0.001). The quantitative ELISA-like immunohistochemistry was a feasible and reproducible procedure to detect the high FGF23 expression in formalin-fixed and paraffin-embedded biopsies or specimens. Since TIO was often delay-diagnosed or misdiagnosed, clinicians and pathologists should be aware of TIO and PMTMCT, respectively.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Neoplasias de Tecido Conjuntivo/diagnóstico , Neoplasias de Tecido Conjuntivo/metabolismo , Adolescente , Adulto , Diagnóstico Diferencial , Diagnóstico Precoce , Ensaio de Imunoadsorção Enzimática , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias de Tecido Conjuntivo/patologia , Osteomalacia , Síndromes Paraneoplásicas , Reprodutibilidade dos Testes , Regulação para Cima , Adulto JovemRESUMO
Phosphaturic mesenchymal tumor (PMT) has been established as a tumor that causes tumor-induced osteomalacia (TIO) associated with mesenchymal neoplasm. Its lineage of differentiation has not been elucidated. Previously, the presence of lymphatic vessels inside PMTs has been documented using an anti-podoplanin antibody; the tumor cells of PMTs were reported to not react with it. In this study of 14 cases of PMTs, we used immunohistochemistry of D2-40, a relatively specific lymphatic endothelial marker, to see if they stained PMTs or not, with particular interest in its reaction with microcystic structures containing lymph-like fluid. We report that most of the PMTs (12 out of 14 cases; 86%) were immunostained by D2-40 in their tumor cells; D2-40-positive lymphatic vessels inside the tumor were also observed. We used a proportion score (0-4+), an intensity score (0-3+), and a total score (the sum of the proportion score and the intensity score) to quantitate our results. We report that 50% of cases (7 out of 14 cases) had a total score ≥ 4+; immunostaining of D2-40 in cases with a total score ≥ 4+ was easy to observe at a glance. Most of the tumor cells lining the microcystic structures were immunostained with D2-40. Thus, D2-40 could be a useful diagnostic marker of PMTs and it might also indicate that PMTs take a lymphatic endothelial immunophenotype.
Assuntos
Anticorpos Monoclonais Murinos/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/diagnóstico , Neoplasias de Tecido Conjuntivo/diagnóstico , Adulto , Idoso , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Diagnóstico Diferencial , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Tecido Conjuntivo/metabolismo , Neoplasias de Tecido Conjuntivo/patologia , Osteomalacia , Síndromes ParaneoplásicasRESUMO
Phosphaturic mesenchymal tumor (PMT) has been elucidated as a cause of tumor-induced osteomalacia (TIO) associated with mesenchymal neoplasm. TIO is associated with the production of phosphatonins, such as fibroblast growth factor 23 (FGF23), which participate in phosphate homeostasis. Fibroblast growth factor receptor 1 (FGFR1) is a known receptor of FGF23, and it was recently found that the fibronectin 1 (FN1)-FGFR1 fusion gene is present in 60% of PMT cases. Immunohistochemical evaluation of FGFR1 expression in PMT has not been reported till date. We analyzed 11 cases of PMT in this study and found that 36% of cases (4/11 cases) exhibited cytoplasmic and membranous staining with strong intensity, and 64% of cases (7/11 cases) exhibited cytoplasmic dot-like staining with moderate to weak intensity. The aforementioned 36% of cases may reflect the presence of the FN1-FGFR1 fusion gene, as the FN1 promoter enhances FGFR1 expression. Although FGFR1 signaling increases FGF23 expression in an autocrine/paracrine loop, FGF23 serum level does not correlate with FGFR1 membranous expression (staining with strong intensity). Thus, we speculate that important factors other than FGFR1 are involved in the tumor biology of PMTs overexpressing FGF23.
Assuntos
Neoplasias Ósseas/metabolismo , Neoplasias de Tecido Conjuntivo/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Neoplasias de Tecidos Moles/metabolismo , Adulto , Idoso , Neoplasias Ósseas/patologia , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Tecido Conjuntivo/patologia , Osteomalacia , Síndromes Paraneoplásicas , Neoplasias de Tecidos Moles/patologiaRESUMO
INTRO/OBJECTIVE: Atypical Fibroxanthoma (AFX) is a rare cutaneous neoplasm arising from myofibroblast or fibroblast-like cells that predominantly affects the head and neck region. It commonly mimics more invasive neoplasms and is a diagnostic challenge to clinicians. The aim of this study was to develop a better understanding of AFX, focusing on recent developments in diagnosis and management. METHODS: A retrospective case series and review of recent literature were carried out. RESULTS: Over a 17-year period, seven cases were identified (six male, mean age at presentation was 75.9 years). Two patients underwent complete excision and five patients had curettage and cauterisation. Two patients developed local recurrence but none demonstrated signs suggestive of metastatic spread. Histologically all seven lesions displayed a spindle cell pattern. Where performed, immunohistochemical staining was positive for Vimentin, CD10, CD68 and actin, and negative for CAM 5.2, CD34, Melan-A, S100 protein, HMB45, Cytokeratin A1/A3. CONCLUSION: Our patient demographics, histopathology and immunohistochemistry are comparable to previous studies. Although advances have been made in immunohistochemical analysis, we are yet to discover a specific diagnostic immunostain for AFX. Clinical findings should therefore be correlated with histology and a panel of immunohistochemical stains should be used. Given the potential for recurrence or metastases, Moh's Micrographic Surgery with regular follow-up may be the preferred management.
Assuntos
Neoplasias de Cabeça e Pescoço/patologia , Recidiva Local de Neoplasia , Neoplasias de Tecido Conjuntivo/patologia , Couro Cabeludo/patologia , Neoplasias Cutâneas/patologia , Actinas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Antígenos CD34/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Biomarcadores/metabolismo , Cauterização , Estudos de Coortes , Curetagem , Feminino , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Queratinas/metabolismo , Antígeno MART-1/metabolismo , Masculino , Pessoa de Meia-Idade , Cirurgia de Mohs , Neoplasias de Tecido Conjuntivo/metabolismo , Neoplasias de Tecido Conjuntivo/cirurgia , Neprilisina/metabolismo , Estudos Retrospectivos , Proteínas S100/metabolismo , Couro Cabeludo/metabolismo , Couro Cabeludo/cirurgia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/cirurgia , Vimentina/metabolismoAssuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Doenças do Pé/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias de Tecido Conjuntivo/metabolismo , Osteomalacia/etiologia , Síndromes Paraneoplásicas/etiologia , Neoplasias Cutâneas/metabolismo , Adulto , Fator de Crescimento de Fibroblastos 23 , Doenças do Pé/complicações , Doenças do Pé/patologia , Humanos , Hipofosfatemia/etiologia , Masculino , Neoplasias de Tecido Conjuntivo/complicações , Neoplasias de Tecido Conjuntivo/patologia , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/patologia , Dedos do Pé , Vitamina D/análogos & derivados , Vitamina D/sangueRESUMO
Bone morphogenetic proteins (BMPs) are multifunctional proteins, and their receptors (BMPRs) have crucial roles in the process of signaling. However, their function in cancer is somewhat inconsistent. It has been demonstrated that more prevalent expression of bone morphogenetic protein receptor 2 (BMPR2) has been detected in dedifferentiated chondrosarcomas than conventional chondrosarcomas. Here, we find that BMPR2 inhibition induces apoptosis and autophagy of chondrosarcoma. We found that BMPR2 expression was correlated with the clinicopathological features of chondrosarcomas, and could predict the treatment outcome. Knockdown of BMPR2 by small interfering RNA results in growth inhibition in chondrosarcoma cells. Silencing BMPR2 promoted G2/M cell cycle arrest, induced chondrosarcoma cell apoptosis through caspase-3-dependent pathway via repression of X-linked inhibitor of apoptosis protein (XIAP) and induced autophagy of chondrosarcoma cells via XIAP-Mdm2-p53 pathway. Inhibition of autophagy induced by BMPR2 small interfering RNA (siBMPR2) sensitized chondrosarcoma cells to siBMPR2-induced apoptotic cell death, suggesting that autophagy has a protective role for chondrosarcoma cells in context of siBMPR2-induced apoptotic cell death. In vivo tumorigenicity assay in mice indicated that inhibition of BMPR2 reduced tumor growth. Taken together, our results suggest that BMPR2 has a significant role in the tumorigenesis of chondrosarcoma, and could be an important prognostic marker for chondrosarcoma. BMPR2 inhibition could eventually provide a promising therapy for chondrosarcoma treatment.
Assuntos
Apoptose , Autofagia , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Condrossarcoma/metabolismo , Neoplasias de Tecido Conjuntivo/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Animais , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Condrossarcoma/genética , Condrossarcoma/fisiopatologia , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias de Tecido Conjuntivo/genética , Neoplasias de Tecido Conjuntivo/fisiopatologia , Estabilidade Proteica , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genéticaRESUMO
Malignant mesothelioma (MM), lung cancers, and asbestosis are hyperproliferative diseases associated with exposures to asbestos. All have a poor prognosis; thus, the need to develop novel and effective therapies is urgent. Vandetanib (Van) (ZD6474, ZACTIMA) is a tyrosine kinase inhibitor that has shown equivocal results in clinical trials for advanced non-small cell lung cancer. However, tyrosine kinase inhibitors alone have shown no significant clinical activity in phase II trials of patients with unresectable MM. Using epithelioid (HMESO) and sarcomatoid (H2373) human MM lines, the efficacy of tumor cell killing and signaling pathways modulated by Van with and without doxorubicin (Dox) was examined. Van alone reduced total cell numbers in HMESO MM and synergistically increased the toxicity of Dox in HMESO and H2373 cells. Most importantly, we identified two novel cell survival/resistance pathways, ERK5 and cyclic AMP response element binding protein (CREB), that were inhibited by Van and Dox. After silencing of either ERK5 or CREB, significant decreases in cell numbers in the Dox-resistant sarcomatoid H2373 line were observed. Results suggest that a plethora of cell signaling pathways associated with cell survival are induced by Dox but inhibited by the addition of Van in MM. Data from our study support the combined efficacy of Van and Dox as a novel approach in the treatment of MM that is further enhanced by blocking ERK5 or CREB signaling cascades.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Doxorrubicina/farmacologia , Sistema de Sinalização das MAP Quinases/fisiologia , Mesotelioma/tratamento farmacológico , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Piperidinas/farmacologia , Quinazolinas/farmacologia , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Doxorrubicina/toxicidade , Sinergismo Farmacológico , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mesotelioma/metabolismo , Proteína Quinase 7 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 7 Ativada por Mitógeno/genética , Neoplasias de Tecido Conjuntivo/tratamento farmacológico , Neoplasias de Tecido Conjuntivo/metabolismo , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Piperidinas/toxicidade , Quinazolinas/toxicidade , RNA Interferente Pequeno/genética , Sarcoma/tratamento farmacológico , Sarcoma/metabolismoRESUMO
Canine cutaneous mast cell tumour (CMCT) is a c-Kit driven tumour sharing similar c-Kit aberrations found in human gastrointestinal stromal tumour. CMCT is classified into three forms: well- (G1), intermediately (G2) (more benign diseases), and poorly (G3) differentiated (malignant) forms. We assess a correlation between c-Kit status, grading, and angiogenesis in CMCTs to explore their potential significance in humans. C-Kit receptor (c-KitR) expression, microvascular density (MVD), and mast cell granulated and degranulated status density (MCGD and MCDD, resp.) were analyzed in 97 CMCTs, by means of histochemistry, immunohistochemistry double staining, and image analysis system. Data showed that predominantly diffuse cytoplasmic- and predominantly focal paranuclear- (Golgi-like) c-Kit protein (PDC-c-Kit and PFP-c-Kit, resp.) expression correlate with high MVD, G3 histopathological grade, and MCDD. Moreover, predominant cell membrane-c-KitR (PCM-c-KitR) expression status correlates with low MVD, G1-G2 histopathological grade, and MCGD. These findings underline the key role of c-Kit in the biopathology of canine MCTs, indicating a link between aberrant c-Kit expression, increased angiogenesis, and higher histopathological grade. CMCT seems to be a model to study contributions of c-Kit activated MCs in tumour angiogenesis and to evaluate the inhibition of MCs activation by means of c-Kit tyrosine kinase inhibitors, currently translated in humans.
Assuntos
Mastócitos/patologia , Neovascularização Patológica/patologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Animais , Doenças do Cão/metabolismo , Doenças do Cão/patologia , Cães , Humanos , Imuno-Histoquímica/métodos , Mastócitos/metabolismo , Microvasos/metabolismo , Microvasos/patologia , Neoplasias de Tecido Conjuntivo/metabolismo , Neoplasias de Tecido Conjuntivo/patologia , Neovascularização Patológica/metabolismo , Neoplasias Cutâneas/patologiaRESUMO
CONTEXT: Localization of phosphatonin-producing mesenchymal tumours in patients with primary tumour-induced osteomalacia (pTIO) is challenging. Functional imaging plays an important role in the localization of these tumours. OBJECTIVE: We studied the relative performance of different functional imaging modalities ((18) F-FDG PET/CT, (99) Tc-HYNIC-TOC SPECT/CT and (68) Ga-DOTATATE PET/CT) in tumour localization in cases of pTIO. DESIGN AND METHODS: Retrospective chart evaluation of 16 patients with confirmed TIO treated from 2006 to 2013 was conducted in a tertiary care referral centre. RESULTS: Of 16, nine patients had pTIO. In these nine, the positivity rates of different functional imaging modalities were 50% for (18) F-FDG PET/CT (four of eight patients), 100% for (99) Tc-HYNIC-TOC SPECT/CT (six of six patients) and 100% for (68) Ga-DOTATATE PET/CT (seven of seven patients). Of nine patients, six were subjected to both the (99) Tc-HYNIC-TOC SPECT/CT and (68) Ga-DOTATATE PET/CT and all of them showed coregistration on the two scans. CONCLUSIONS: In patients with pTIO, the somatostatin receptor-based functional scans performed better than (18) F-FDG PET/CT in tumour localization. Amongst the somatostatin receptor-based scans, (99) Tc-HYNIC-TOC SPECT/CT and (68) Ga-DOTATATE PET/CT performed equally well for localization of tumours.
Assuntos
Fluordesoxiglucose F18 , Neoplasias de Tecido Conjuntivo/diagnóstico , Neoplasias de Tecido Conjuntivo/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Receptores de Somatostatina/metabolismo , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Tecido Conjuntivo/cirurgia , Osteomalacia , Síndromes Paraneoplásicas , Estudos Retrospectivos , Adulto JovemRESUMO
Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome associated with tumors that secrete phosphaturic hormones, most notably fibroblast growth factor 23 (FGF23). The majority of tumors associated with this syndrome show stereotypical histological features and are now known as phosphaturic mesenchymal tumors (PMTs). We postulated that immunohistochemistry for somatostatin receptor 2A (SSTR2A) could be used to definitively identify PMTs or other tumors that cause TIO. Immunohistochemistry for FGF23 and SSTR2A was performed on 15 tumors from 14 patients with a definite diagnosis of TIO. All showed positive staining for both markers. While FGF23 staining was quite focal in some tumors, SSTR2A showed diffuse strong expression. In 40 control tumors not known to be associated with the clinical or biochemical features of TIO, FGF23 expression was found in 2 cases (one aneurysmal bone cyst and one osteosarcoma). SSTR2A expression was found in 9 control tumors (4 synovial sarcomas, 2 hemangiomas, 2 aneurysmal bone cysts and one osteosarcoma). Only one tumor (an aneurysmal bone cyst) showed positive staining for both FGF23 and SSTR2A. SSTR2A also commonly stained neoplastic and non-neoplastic endothelial cells. We conclude that neither FGF23 nor SSTR2A expression are specific for the diagnosis of PMT. However both stains are highly sensitive. Because of its diffuse strong expression and widespread availability, immunohistochemistry for SSTR2A is useful to confirm the diagnosis of PMT in an appropriate setting particularly if material is limited. Negative staining can serve as an excellent rule out test for this diagnosis.
Assuntos
Hipofosfatemia Familiar/diagnóstico , Mesenquimoma/diagnóstico , Neoplasias de Tecido Conjuntivo/diagnóstico , Osteomalacia/diagnóstico , Síndromes Paraneoplásicas/diagnóstico , Receptores de Somatostatina/metabolismo , Adulto , Medicamentos de Ervas Chinesas , Eleutherococcus , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Hipofosfatemia Familiar/metabolismo , Hipofosfatemia Familiar/patologia , Masculino , Mesenquimoma/metabolismo , Mesenquimoma/patologia , Pessoa de Meia-Idade , Neoplasias de Tecido Conjuntivo/metabolismo , Neoplasias de Tecido Conjuntivo/patologia , Osteomalacia/metabolismo , Osteomalacia/patologia , Síndromes Paraneoplásicas/metabolismo , Síndromes Paraneoplásicas/patologiaRESUMO
Phosphaturic mesenchymal tumors of the mixed connective tissue type (PMT-MCTs) are rare neoplasms, most of which are benign and cause tumor-induced osteomalacia because of overproduction of a phosphaturic hormone, fibroblast growth factor 23 (FGF23). This entity may have been unrecognized or misdiagnosed as other mesenchymal tumors, such as giant cell tumor, hemangiopericytoma, and osteosarcoma. Ten percent of these tumors, without phosphaturia, were diagnosed only by their histologic features. We report here the first case of malignant PMT-MCT, nonphosphaturic variant, resulting in fatal multiple lung metastases. Chondromyxoid matrix with "grungy" calcification, multinucleated giant cell proliferation, and expression of FGF23 mRNA (reverse transcription-polymerase chain reaction) and fibroblast growth factor 23 protein (immunohistochemistry) were seen in the primary and recurrent tumors of the right foot. The lung metastases showed flocculent calcification and FGF23 protein expression as well as giant cell proliferation. This unique case highlights the need for careful histologic assessment of PMT-MCTs, especially the nonphosphaturic variant, and the need for recognition of its rare malignant behavior.